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Some pharmacological and microbiological studies on beta-hydroxy thujaplicin Sanders, Harvey David


Beta-hydroxy thujaplicin (BHT) is a naturally occurring tropolone found in the heartwood of the Western Red Cedar (Thuja plicata D.Don.). It has been found to possess both stimulatory and depressant components, depending on the dose, when administered to mice. It has also been shown to increase the toxicity of lead and in limited microbiological studies, it was found to be both bacteriostatic and fungistatic in vitro. The stimulant effects of BHT were manifest in mice by a hyperexcitability and in larger doses by convulsions. In rabbits, the convulsive pattern was obtained in EEG studies. Mice which exhibited convulsions or an intense degree of hyperexcitability in the absence of convulsions, invariably died. In this respect BHT differs from gamma-thujaplicin, where doses just sufficient to produce convulsions are not lethal. The intraperitoneal LD₅₀ and CD₅₀ (convulsive dose) in mice were found to be 155 ± 4.5 mgm/Kg. and 163 ± 6.2 mgm/Kg. respectively, which indicates that a convulsive dose differs little from a lethal dose. A period of depression always followed the convulsions and was manifest by ptosis, decreased respiration and hypokinesia. Death occurred in this stage. Convulsions were prevented by thiopental and hexobarbital but barbiturate sleeping time was not decreased - in fact it was increased. Hexobarbital exerted a protective effect against lethal doses of BHT whereas thiopental delayed but did not prevent death. The ability of BHT to prolong sleeping time was not extended to ethanol. In smaller doses, BHT exhibited depressant effects manifested by hypothermia, hypokinesia and ease in handling. The hypothermic action was most pronounced at room temperatures and sedation was found to be proportional to the magnitude of the temperature fall. A synergistic action as to hypothermia and hypokinesia was observed with chlorpromazine and to a lesser extent with reserpine. At elevated ambient temperatures, animals treated with BHT exhibited hyperthermia and hyperkinesia. At normal temperatures BHT further increased the hyperthermia produced by amphetamine, but antagonized the hyperkinetic effect. Ultimately, however, the temperature of these animals was depressed to a greater degree than was the activity. The point of maximum antagonism to the hyperkinetic effect of amphetamine occurred approximately one hour following administration of BHT, while the maximum hypothermic effect of BHT was delayed an additional two hours. BHT-Na (sodium salt of BHT) when administered intravenously or intra-arterially in rabbits, caused a precipitous rise in blood pressure. This pressor response appeared to be unrelated to the low voltage-fast activity pattern observed on the EEG. BHT exhibited both bacteriostatic and fungistatic properties when tested in vitro against a wide variety of organisms. However, it was found to be inactive against D. pneumoniae when tested in vivo. A possibility exists that BHT is inactivated by whole blood. The toxicity of lead salts was found to be increased by BHT. This action is probably due to the formation of an insoluble chelate, promoting lead retention in the tissues and increasing its uptake from the body fluids. The toxicity of lead acetate was increased by two-thirds In the presence of BHT. Preformed lead chelate of BHT produced no observable toxic symptoms in the doses tested.

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